The field of the invention is recombinant DNA technology. The invention is particularly concerned with a genetic control element derived from an adenovirus.
The control region of the adenovirus genome and its relation to the E1A gene has been extensively studied. It is known that the protein products of the adenovirus E1A gene may act as positive and negative regulators of early viral gene expression, and that E1A products regulate at the transcriptional level. Sequences located 5' to the early viral regions contain sites which confer regulation by the E1A gene product. Weeks and Jones, Mol. Cell. Biol. (1983), 3:1222-1234. Positive and negative autoregulation of the adenovirus E1A gene transcription has been reported. Tibbetts et al., J. Virol. (1986) 57:1055-1064.
The E1A control region and E1A gene for adenovirus type 3 (Ad3) have been incorporated in plasmid vectors; the Ad3 control region and Ad3 E1A gene have been sequenced. Kosturko, et al., J. Virol. (1982), 43:1132-1137. Variant genomes of the Ad3 control region have been produced by repeated passage of the adenovirus in HeLa cells. Robinson and Tibbetts, Virology (1984), 137:276-286. The reported variations occurred in the left-most 750 bp of the genome. However, the mutants retained the first 135 bp, comprising the inverted terminal repeat region (ITR) of the Ad3 strain. In particular, the variations occurred in the 440 bp between the ITR and the initiation codon (AUG) at bp 575.
The sequences between ITR and AUG have been shown to include enhancer sequences for adenovirus type 5. Hearing and Shenk, Cell (1983), 33:695. The two enhancer fragments found by these authors were composed of different nucleotide sequences, and were separated from each other by intervening DNA.